Glutamate which is the most important excitatory neurotransmitter in the central nervous system of mammals plays an important role in maintaining the normal function of nervous system and also plays an important role in many pathophysiological processes such as pain, neurodegenerative lesions and epilepsy. At the same time, the massive release and accumulation of glutamate in the nervous system is the pathology basis of a variety of nerve cell damage and neurodegenerative disease, i.e., the neurotoxic effect of glutamate, eventually leading to neuronal death. The excitotoxicity lead by glutamate activating its receptor and the oxidative toxicity lead by inhibiting of glutamate/cystine transporters on the cell membrane are the origins of many nervous system diseases such as cerebral ischemia, Parkinson's disease, epilepsy, thus making glutamate receptors become one of the therapeutic targets of these diseases.
Glutamate receptors (GluR) are mainly divided into ionotropic glutamate receptors (iGluRs) and metabotropic glutamate receptors (mGluRs). The ionotropic glutamate receptor antagonist has achieved some therapeutic effect in the animal model by directly blocking the postsynaptic effect of glutamate, but it also blocks normal excitatory transmission and produces serious side effects, such as psychiatric symptoms, dizziness, fatigue, etc., thus limiting the clinical application of such compounds; and metabotropic glutamate receptors inhibit the release of glutamate through the presynaptic mechanism, thus reducing the toxic and side effect of ionotropic glutamate receptor antagonist, and are expected to become a new target for the treatment of certain neurological diseases.
mGluRs is one of the members of the C family of the G protein coupled receptors (GPCRs) superfamily. According to its protein sequence homology, receptor-coupled second messenger system signal transduction mechanism and specificity for different agonists, it can be divided into three categories. The first category mGluRI (mGluR1, mGluR5) mainly is distributed in the postsynaptic region, the mGluR1 receptors are also distributed in the glial cells, and the mGluR5 receptors are distributed in the marginal cortex and basal ganglia, which are closely related to the morphology of dendritic spines and play an important role in synaptic transmission and plasticity. The second category mGluR II (mGluR2, mGluR3) mainly locates in the presynaptic region, wherein mGluR2 receptors locate in the cerebellum, cerebral cortex, thalamus synaptic axons, mGluR3 receptors are also widely distributed in the brain, including glia. The third category mGluRIII (mGluR4, mGluR6, mGluR7, mGluR8) is also distributed in the presynaptic region, mGluR 4/7/8 locates in the basal ganglia movement loop, and mGluR6 receptors are in the retinal neurons. There is about 70% homology in the same mGluR group, and only about 45% homology between the different groups. mGluR5 mainly locates in the neuronal postsynaptic excitatory terminal and glia, couples with Gα/q protein, activates phospholipase C, and enhances intracellular Ca2+ release. Studies have shown that mGluR5 is highly expressed in the central nervous system (CNS), mainly in the areas associated with the nervous system and mental illness such as cerebral cortex, hippocampus and basal ganglia, etc. Thus, mGluR5 is one of the important targets for the treatment of central nervous system and psychiatric-related diseases.
Regarding to the design of medicine to the target, early studies mainly focused on the design of small molecule competitive antagonists for endogenous ligands, but because of the high conservation degree of the mGlu receptor binding sites, it is difficult to obtain a compound having good selectivity to receptor subtypes. In addition, many endogenous ligands are often glutamic acid derivatives, lacking suitable pharmacokinetic properties and CNS permeability makes these compounds difficult to use in clinical research. In recent years, allosteric modulators of mGlu receptors have attracted widespread attention. Compounds bind to non-endogenous ligand sites, do not directly activate or antagonize receptor function, but indirectly increase or decrease glutamate-induced activity, known as positive allosteric modulators (PAMs) and negative allosteric modulators (NAMs). mGlu receptor allosteric modulators act on the allosteric sites of the GPCR transmembrane region, thus providing greater possibilities for overcoming defects in the selectivity and poor permeability of the mGlu receptor endogenous site competitive antagonists.
In recent years, mGluR5 negative allosteric modulator has caused great concern of the majority of scientific research workers and major pharmaceutical companies as a potential treatment drug for fragile X chromosome syndrome, such as Parkinson's disease levodopa-induced dyskinesia (PD-LID), gastroesophageal reflux disease (GERD), autism, pain, anxiety, depression, drug addiction and the like. Since 2000, there have been more than 190 mGluR5 negative allosteric modulator patent applications, of which 66 patent applications are filed from 2009 to June 2013; so far at least 9 small molecules have entered the clinical trials, of which 4 compounds are currently undergoing II or III clinical trials such as Mavoglurant, Diproglurant, RG7090 and Fenobam. Therefore, mGluR5 negative allosteric regulatory site is regarded as ideal drug target, while designing novel mGluR5 negative allosteric modulator for the treatment of the central nervous system and psychiatric system-related diseases on this basis has very important significance and good application prospects.
In summary, there is an urgent need in the art for the development of novel mGluR5 negative allosteric modulator.